A major focus of our efforts is on the roles played by the IL-2/IL-2R and IL-15/IL-15R systems in the life and death of T cells and the use of these insights to develop IL-2R and IL-15R directed therapies for leukemia and autoimmune diseases. Previously, we defined the IL-2 receptor subunits, IL-2/IL-15R beta and IL-2R alpha, using the first ever reported anti-cytokine receptor monoclonal antibody (anti-Tac, daclizumab) that was developed in our laboratory. These seminal studies on the IL-2 receptor have culminated in the definition of the IL-2R as an exceptionally valuable target for the therapy of leukemia and for autoimmune diseases. We introduced different forms of IL-2 receptor directed therapy using agents we developed including unmodified murine antibodies to IL-2R alpha (anti-Tac), humanized anti-Tac (daclizumab), the first antibody directed toward a cytokine receptor to receive FDA approval and this antibody armed with toxins or beta and alpha-emitting radionuclides. In clinical trials we demonstrated that anti-Tac (daclizumab) provides effective therapy for a subset of patients with HTLV-I associated adult T-cell leukemia (ATL). The leukemic cells are of the CD4+ CD25+ phenotype, that profoundly suppress immune responses. In a clinical trial that included ATL patients and that involved anti-Tac armed with 90Y we observed remissions in over 50% of trial patients who had this previously universally fatal leukemia/lymphoma. Furthermore of 23 patients with refractory Hodgkins disease treated with 90 Y labeled daclizumab 14 manifested a complete response and an additional 2 a partial response. We and our collaborators demonstrated that there was a 78% reduction in gadolinium-enhanced MRI lesions in patients with multiple sclerosis who are failing beta interferon therapy when they were treated with humanized anti-Tac (daclizumab). On the basis of these studies, placebo controlled double blind trial of daclizumab in over 200 patients have validated the reduction in new MS lesions observed in the initial trials. Clinical responses have been paralleled by a 4-20 fold increase in the number of circulating immunoregulatory CD56BrightCD16negative NK cells. Furthermore, we demonstrated effective therapy in this murine model of ATL with the anti-CD2 monoclonal antibody MEDI-507 as well as with the anti-CD52 monoclonal antibody CAMPATH-I. On the basis of these encouraging preclinical results, clinical trials have been initiated by the Metabolism Branch Clinical Trials Team with anti-Tac (daclizumab) and CAMPATH-I. Remissions have been observed with both of these monoclonal antibodies. In a most critical development, as part of our studies of IL-2 receptor directed therapy for HTLV-I associated ATL, we co-discovered a lymphokine, IL-15, that is required for the development and maintenance of NK-cells as well as CD8 memory phenotype T-cells. Furthermore, we demonstrated that the cytokines IL-2 and IL-15 that share two receptor subunits manifest distinct contributions to immune responses. IL-2 through its pivotal role in the generation and survival of CD4+ CD25+ Tregs (suppressor cells) and activation-induced cell death (AICD) is involved in the T-cell suicide required for self tolerance. In contrast, IL-15 inhibits AICD and favors the survival of CD8 memory cells and is thereby dedicated to the persistence of immunological memory to invading pathogens. IL-15 expression have been demonstrated in patients with an array of autoimmune diseases and T-cell leukemias. We are translating this observation by the introduction of humanized Mik-Beta-1 directed toward IL-2/IL-15R beta that blocks IL-15 action into clinical trials involving these disorders. Our observations on the role of IL-15 in immunological memory are critical for the rational use of this cytokine in the treatment of cancer and as a component of vaccines. Our group, in collaboration with the Berzofsky group, demonstrated that the co-administration of an HIV vaccinia virus vaccine expressing IL-15 induced long-lasting CD8 cytotoxic T-lymphocyte mediated immunity. In contrast, T-cell immunity mediated by IL-2 was short-lived. The IL-15 environment at the time of immunological priming had persistent effects on the character of the memory CD8 T-cells long afterwards. In further studies, it was demonstrated that a vaccinia vaccine vector expressing IL-15 induced high-avidity cytotoxic lymphocytes(CTL) that expressed high levels of IL-15R alpha, the private receptor for IL-15. On the basis of these studies, we have suggested that the incorporation of IL-15 as a component of molecular vaccines may represent a major advance in the generation of agents that yield long-lasting immune responses. To test this hypothesis, molecular vaccines that include IL-15 in association with HIV, HER-2/neu, anthrax and tuberculosis have been generated to yield agents that will be evaluated in trials focusing on the prevention and treatment of chronic infectious diseases and cancer. We are also evaluating the introduction of IL-15 in the treatment of neoplasia. In preclinical studies we demonstrated that IL-15 transgenic mice in contrast to wild-type mice did not develop the colon carcinoma (MC38) following intravenous introduction of the cancer cells and that MC38 cells transfected with IL-15R alpha no longer formed metastases in wild-type mice. These findings provide the scientific basis for the use of IL-15 in lieu of IL-2 in the treatment of select malignancies and for the incorporation of IL-15 into molecular vaccines for cancer and AIDS. In a seminal observation we demonstrated that IL-15 bound to IL-15R alpha on antigen presenting cells as presented in trans to target NK and CD8 cells that express the other IL-15 receptor subunits beta and gamma. In translation of this observation we have demonstrated that addition of an agonist antibody to CD40 increases IL-15R alpha expression and augments IL-15 efficacy in murine syngeneic tumor models. IL-15 is a dangerous cytokine in that it stimulates the production of TNF-alpha, IL-1-beta and inflammatory chemokines, inhibits IL-2 mediated AICD and favors the persistence of CD8 memory cells. Abnormalities of IL-15 expression have been described in inflammatory autoimmune disorders and CD8 T-cell leukemia/lymphoma as well as HTLV-I associated diseases. We have introduced antibodies to the IL-2/IL-15R beta subunit to prevent the transpresentation of IL-15 and thereby inhibit IL-15 action. We have used an antibody TMbeta-1 (anti-IL2/IL-15Rbeta) to inhibit such IL-15 transpresentation in mice. Our treatment of mice with TMbeta-1 resulted in the rapid (within 2 days) 90% depletion of NK cells and 70% reduction in the number of dendritic and CD44hi CD8+ memory phenotype T-cells. We are utilizing this antibody in preclinical therapeutic trials in a series of autoimmune disorders of mice. We have produced humanized Mik-beta-1 that is directed to human IL-2/IL15R beta (CD122) to block IL-15 action and have shown that it prolongs cardiac allograft survival in Cynomolgus monkeys. A clinical trial is underway using Hu-Mik-Beta-1 in the study of CD8 positive T-cell large granular lymphocytic leukemia. Additional collaborative clinical trials are being initiated to evaluate this monoclonal antibody and in patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Trials are being planned with this agent in patients with rheumatoid arthritis, multiple sclerosis and refractory celiac syndrome associated with premalignant and malignant CD8 T-cell lymphoma. Thus, these insights concerning IL-2/IL-2R and IL-15/IL-15R systems are providing the scientific basis for translation into novel therapies for patients with lymphoid malignancies and autoimmune disorders